Ex Vivo Effect of Apixaban on Hemostatic Biomarkers in Children With Heart Disease: A SAXOPHONE Trial Substudy

The SAXOPHONE (Safety of Apixaban on Pediatric Heart Disease on the Prevention of Embolism) trial demonstrated the safety of apixaban for thromboprophylaxis in children with heart disease. Included a priori in the trial design was an exploratory biomarker substudy to evaluate the effects of apixaban on surrogate biomarkers of efficacy, thrombin generation capacity, and hemostatic proteins. The study assessed changes in d-dimer, thrombin generation assay parameters, factor VIII, fibrinogen, protein C, and protein S in children receiving apixaban compared with standard-of-care vitamin K antagonists (VKAs) or low-molecular-weight heparin.

SAXOPHONE participants aged >1 year (n=182) had blood samples for biomarkers collected at baseline, week 2, or month 6. Participants were randomized to apixaban (n=123) or standard of care (VKA or low-molecular-weight heparin; n=59). Subgroup analyses accounted for prior VKA exposure.

d-dimer levels decreased at month 6 in all treatment groups and remained stable during VKA-to-apixaban bridging. Apixaban significantly prolonged thrombin generation assay lag time and time to peak compared with VKAs and decreased peak thrombin similarly to VKAs in anticoagulant-naïve participants. Apixaban was associated with decreased fibrinogen and factor VIII at month 6, with no effect on protein C or S. Prior VKA exposure produced carryover effects, suppressing baseline d-dimer, thrombin generation assay parameters, and proteins C and S.

Apixaban reduced hypercoagulability, as shown by decreased d-dimer levels and prolonged lag time, and preserved endogenous thrombin potential in thrombin generation assay, changes consistent with adult data. These findings align with SAXOPHONE's primary outcomes, supporting apixaban's favorable risk-benefit profile as a thromboprophylaxis option in children with heart disease.